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A 51��Ʒ��Ƶ-led neurobiological expedition to explore a little-known brain region could show the way to new therapies for Parkinson’s disease. The inter-institutional team, funded by a $12 million, 3-year grant from the Aligning Science Across Parkinson’s (ASAP) initiative, will investigate brain circuits they suspect are involved in a placebo effect occasionally seen in the movement disorder.

In a , a man with the stooped posture, shuffling gait and hand tremors characteristic of Parkinson’s gets on a bicycle and then effortlessly pedals around a parking lot. As soon as he hops off his bike, though, the man’s movement challenges reappear.

“This is an example of paradoxical kinesia, or the remarkable return of apparently normal motor function that can occur for some Parkinson’s patients under special circumstances, such as the ability to quickly respond to a fire alarm,” said Principal Investigator , chair of the Department of Neurobiology and scientific director of 51��Ʒ��Ƶ’s . He and his collaborators believe they may know why this happens.

Parkinson’s disease occurs due to the death of nerve cells in a small brain area called the substantia nigra, part of the collections of nerve cells at the base of the brain known as the basal ganglia that interacts with the cerebral cortex through two prominent networks.

One network forms a closed-loop neuronal circuit: a center within the basal ganglia sends outputs to a region in the cortex, which then sends input back to it. This circuit is damaged in Parkinson’s, and motor symptoms of the disease are treated with implanted electrodes, known as deep brain stimulation, at a node within this circuit.

The second network forms an open-loop circuit that receives input from brain sites such as the amygdala that are largely unaffected by Parkinson’s. The 51��Ʒ��Ƶ team suspects that the open-loop circuit provides the pathway for paradoxical kinesia and the placebo effect — its activation allows signals to reach the cerebral cortex and bypass the disease-affected closed-loop circuit.

“For some patients, placebos can be surprisingly effective in treating the movement disorders associated with the disease,” said Strick. “We think there is brain circuitry that makes this possible, so we plan to define it and explore its potential impact on Parkinson’s.”

In the multiprong effort, Strick will map both circuits using his pioneering techniques that harness the transneuronal transport of rabies virus as a pathway tracer. Robert Turner, a professor of neurobiology in 51��Ʒ��Ƶ’s School of Medicine, will examine and manipulate neuron activity in the two circuits in normal and parkinsonian monkeys. Helen Schwerdt, an assistant professor of bioengineering, will examine dynamic aspects of dopamine release in these animals, and William R. Stauffer, an assistant professor of neurobiology, will use single-cell tools to characterize cell-type-specific gene expression and regulation in the two circuits before and after dopamine depletion.

The 51��Ʒ��Ƶ investigators are joined by Scott Grafton of the University of California Santa Barbara, who will use functional MRI scanning to examine emotion–motor interactions within the two circuits in humans with and without Parkinson’s disease.

Strick said that examining and characterizing the open-loop circuit could not only identify new locations for deep brain stimulation placement that improve symptoms and minimize side effects, but also lead to the discovery of new treatments for Parkinson’s disease.

The Aligning Science Across Parkinson’s initiative is a coordinated research initiative to advance targeted basic research for Parkinson’s disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources and data sharing. The Michael J. Fox Foundation for Parkinson’s Research is ASAP’s implementation partner and issued the grant.

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— Anita Srikameswaran